Tissue paper. Cobwebs. Butterfly wings.

This is the level of skin fragility experienced by patients with recessive dystrophic epidermolysis bullosa (RDEB), a condition that causes continuous blistering, excruciating wounds, and scarring that can cover more than 30% of the body surface and even up to 80% in extreme instances. Those who are born with a mutation in the COL7A1 gene, which codes for Type VII collagen, experience a life of constant physical and mental agony. Even moving from one place to another or touching an object can cause excruciating pain. Managing the endless wounds caused by the fractured, fragile skin is a common focus of current RDEB therapies, which necessitate frequent and expensive interventions.

Prademagene zamikeracel, or ZEVASKYN, is the first autologous gene-edited cell therapy for RDEB to be approved by the FDA. The approval is based on the pivotal Phase 3 VIITAL study, showing that just a single application of the credit card-sized living treatment could safely heal chronic wounds. At six months, 81% of the 43 large, chronic wounds treated with a single application of ZEVASKYN had healed 50% or more (P<0.0001), compared to 16% of 43 matched control wounds treated with standard care. The most common adverse events were observed in fewer than five percent of patients and included procedural pain and itch, but, in general, the treatment reduced pain.

This approach not only reduces the burden on patients but also significantly lowers healthcare costs over time. “The beauty of this therapy is it’s a one-time therapy with years of benefit, unlike a lot of redosable therapies where you have to chronically treat patients,” Vishwas Seshadri, MD, MBA, CEO of Abeona Therapeutics, told Inside Precision Medicine. “The treated wounds exhibit significant healing—defined as substantial wound closure and regeneration—within six weeks, and these effects can last for years. This is not just a medical achievement; it’s a life-changing intervention.”

The outcomes represent a profound improvement in quality of life for individuals who have long endured the relentless challenges of RDEB and provide an opportunity to restore a semblance of normalcy, allowing patients to reclaim their lives from the relentless grip of this debilitating disease and see a future with hope, healing, and possibility. “Meeting families and seeing the impact of ZEVASKYN firsthand has been incredibly humbling,” Seshadri said. “It’s not just about healing wounds; it’s about restoring dignity, reducing suffering, and giving patients a chance to live more freely.” Recalling one family’s reaction, Seshadri said, “They described it as nothing short of a miracle. For the first time in years, their child could sleep without pain. That moment stays with you.”

The autologous gene-edited cell therapy is scheduled to be available through Qualified Treatment Centers beginning in the summer of 2025.

Butterfly effect

The story of ZEVASKYN began over a decade ago at Stanford University, and the preclinical effort to work with autologous keratinocytes—culturing and making sheets out of them—dates back even further. Early studies demonstrated the feasibility of introducing the COL7A1 gene into keratinocytes to address the underlying cause of RDEB, and the first clinical trials from ZEVASKYN started in 2014.

After the Phase 1/2 studies in 2017, Abeona chose to license the technology from Stanford, bringing it to headquarters in Cleveland, Ohio. But the tech transfer process took longer than expected. Between 2018 and 2019, Abeona learned the know-how for taking the autologous cells using a biopsy from these patients, growing them into sheets, and optimizing that process to turn it into a commercial therapy.

“Abeona decided to pursue ZEVASKYN with the intent to commercialize,” said Seshadri. “It’s always tricky for a product like this, and you have to take the transfer and develop a process that would be regulatory kosher and implement all those changes when you’re learning about it. The FDA is going to ask, “Is that product the same as the one you’re making?” You have to demonstrate bridging everything—the retroviral vector, as well as the drug product, which is skin sheets.”

It wasn’t until 2020, six years after the Phase 1/2 started, that the first patient was dosed for the VIITAL Phase 3 study. Around that time, Seshadri joined Abeona Therapeutics as head of clinical development, regulatory, and research. Then, the unexpected happened. Three months later, he became the CEO. “Those were not the easiest days at the company—they were very challenging,” said Seshadri. “The CEO and much of the management team left, leaving us with only three months of cash.”

Seshadri was able to guide the VIITAL Phase 3 study through its primary endpoint readout in late October 2022, and the data looked great. Just when everything looked like Seshadri and Abeona were back onto stable footing, they received a complete response letter (CRL) from the FDA saying that the approval was denied. But it wasn’t all bad news. “The FDA had no problem with clinical data—it was purely related to CMC,” said Seshadri. “We got a laundry list of things to do, and we did all that and submitted.”

Seshadri added, “Navigating regulatory and manufacturing hurdles required unparalleled dedication. We bridged clinical data across studies, optimized our production methods, and collaborated closely with the FDA to meet rigorous standards. Every challenge we faced reinforced our determination to bring this therapy to the patients who need it most.”

Behind the scenes

Creating ZEVASKYN is a process steeped in precision and innovation, designed to address the unique challenges of recessive dystrophic epidermolysis bullosa (RDEB). Every step of the manufacturing and delivery process ensures the cellular sheets deliver the therapeutic benefits they promise.

ZEVASKYN starts with local anesthesia and a punch biopsy 0.8 centimeters big to obtain skin samples with both the dermis and epidermis, which is then shipped to Cleveland, Ohio. As soon as it arrives, Abeona’s manufacturing team separates the epidermis and dermis and isolates keratinocytes from the biopsy, which are cultured until the cells reach the population size required for the retroviral transduction. The scientists genetically modify the sample cells to express collagen VII, a protein vital for anchoring the dermis to the epidermis. These modified cells undergo stringent quality testing before moving to the next stage.

“We test each sample to determine the proportion of cells that stain positively for collagen VII,” explained Dr. Vishwas Seshadri, CEO of Abeona Therapeutics. “It’s not just about making sure the cells are producing collagen; we’re looking for the collagen trimer, which forms the anchoring fibrils that work in the body. This is the potency test for us—it ensures that the genetically engineered cells are effective.”

Once approved, the cells are expanded and seeded into single-well plates shaped like credit cards. These plates allow the cells to grow into multi-layered sheets through a carefully managed process involving growth and differentiation media. “Initially, we use a growth medium that encourages cell replication,” Dr. Seshadri described. “Later, we switch to a differentiation medium that promotes tight junctions between the cells, creating durable sheets ready for transplantation.”

When the sheets reach maturity, they are harvested and carefully packaged. This involves transferring them onto petrolatum gauze, placing them in specialized Fenwal bags filled with preservation medium, and securing them within clamshell containers for transport. “Our QC personnel hand-deliver these precious packages to treatment centers,” noted Dr. Seshadri. “It’s an intricate process because we have to ensure the sheets arrive intact and ready for surgical application.”

The application of ZEVASKYN sheets in the operating room is a delicate and exacting procedure. Surgeons begin by debriding the patient’s wounds, removing crusts and scar tissue to create a uniform wound bed. The ZEVASKYN sheets, still tethered to their petrolatum gauze, are then sutured to the treated area using titanium clips.

“The suturing process ensures the grafts adhere properly,” Dr. Seshadri explained. “The gauze and clips typically fall off within five to seven days, allowing the new skin to integrate seamlessly.” During this period, patients remain in the hospital, not for safety monitoring but to immobilize the grafted areas and optimize healing conditions.

Unlike other advanced therapies, ZEVASKYN does not require monitoring for immune responses like cytokine release syndrome. “Our focus is on ensuring patients are caring for their grafts appropriately and protecting the fragile new skin,” Dr. Seshadri emphasized. This meticulous process, from cell culture to surgical application, highlights the extraordinary complexity behind ZEVASKYN’s development. Yet, for patients, it offers a simple promise: the chance to heal.

AIM higher

ZEVASKYN, however, is limited in terms of potential applications beyond this condition. One promising avenue is the treatment of mitten deformities, a severe complication of RDEB where fingers fuse due to the constant formation of scar tissue, making everyday tasks, such as feeding themselves or brushing their hair, challenging. Restoring hand functionality could dramatically improve the lives of RDEB patients, offering newfound independence. These advancements not only enabled ZEVASKYN’s approval but also set a new benchmark for future cell and gene therapies. “The lessons we’ve learned and the infrastructure we’ve built will pave the way for other innovative treatments,” Dr. Seshadri added.

Abeona has only lightly explored how to apply the ZEVASKYN approach to other conditions. They are concentrating more on using their AIM capsid library, which takes advantage of the special biology of adeno-associated viruses (AAVs) to accurately deliver genetic material to specific areas in the body, such as the brain, lungs, eyes, muscles, and liver. These cutting-edge vectors are non-replicating and designed to sidestep immune responses triggered by naturally occurring AAVs, offering a promising solution to one of gene therapy’s most significant challenges: redosing.

AIM vectors circumvent pre-existing immunity, allowing patients who have previously undergone AAV-based therapies to receive additional treatments for conditions that may require multiple interventions over time. Besides being able to give multiple doses, the AIM capsid library has significant benefits like targeting specific tissues, offering different ways to deliver treatments, and removing the risks of replication. This innovation reflects a critical step forward in advancing gene therapy’s safety, efficacy, and accessibility, enabling transformative outcomes for a broader range of patients.

The company is already leveraging its AAV expertise to develop in-house programs for other conditions, including advances in ophthalmology. Abeona has preclinical programs for X-Linked Retinoschisis (XLRS), Stargardt Disease, and Autosomal Dominant Optic Atrophy (ADOA). For neurological rare diseases, Abeona has partnered with Ultragenyx Pharmaceutical on Sanfilippo Syndrome Type A (MPS IIIA) and Taysha Gene Therapies on Rett Syndrome and Infantile Batten Disease (CLN1 Disease), all of which are in Phase 1/2.

“From a therapeutic area standpoint, it may look like a pivot, but we also don’t want to be a cocoon that’s only a rare disease company forever,” said Seshadri. “I believe that a diversified portfolio, encompassing not only rare diseases but also other types, enhances the model’s effectiveness.”

Abeona has reported a very interesting tropism of these capsids in certain compartments of the eye, which, according to Seshadri, nobody has been able to do the way they have. “In past years, we’ve demonstrated in non-human primates that with pretty reasonable quantities, you have high transduction efficiency in the optic nerve and maculae, and that is very attractive for certain retinal diseases. Next week, our team is presenting some groundbreaking preclinical data at the Association for Research in Vision and Ophthalmology (ARVO). We’re excited about it.”

Whether through advanced AIM capsid gene therapies or expanding ZEVASKYN’s applications, the company will continue seeking to shape a world where cutting-edge science delivers hope across conditions once deemed untreatable. The introduction of the first ZEVASKYN treatments in 2025 will undoubtedly transform the lives of patients suffering from RDEB. Abeona has begun to flutter its wings, and even if it doesn’t cause a storm throughout the world, it will have certainly changed the lives of many RDEB patients in ways that weren’t possible before.